The pro-inflammatory cytokine TNFα has a crucial role in inflammation, immune responses, and apoptosis (1-4). TNFα alone does not typically induce apoptosis under physiological or developmental conditions unless IKK-mediated activation of NF-κB is also impaired (5) because the target gene products of NF-κB inhibit caspases and prevent prolonged JNK1 activation (6, 7). Inactivation of the BH3-only family protein BAD by IKK is also required for suppression of TNFα-induced apoptosis (8). Like other BH3-only family member proteins, BAD is a potent inducer of apoptosis (9). Hypo-phosphorylated BAD translocates from the cytosol to mitochondria to inactivate the anti-apoptotic BCL-2 family members BCL-2 and BCL-xL, which results in the increased activity of the pro-apoptotic BCL-2 family members BAK and BAX to induce apoptosis (10, 11). Phosphorylation of BAD by IKK at Ser26 primes BAD to be further phosphorylated at Ser112, Ser136, and Ser155 by other protein kinases (e.g., Akt and PKA), which results in the sequestration of BAD in cytosol by association with the phospho-Ser/Thr anchoring protein 14-3-3 (8, 10-12).
TNFα cytotoxicity has long been recognized to have a crucial role in the pathologies of inflammatory disease, infectious disease, autoimmune disease, and cancer (13, 14). However, the mechanism underlying TNFα cytotoxicity is not known. Furthermore, little is known about the genetics and chemical perturbations of TNFα cytotoxicity and IKK signaling pathways in diseases associated with TNFα-induced tissue or organ damage.